One-pot hydrogen peroxide and hydrohalic acid induced ring closure and selective aromatic halogenation to give new ring-fused benzimidazoles

A new series of selectively dichlorinated and dibrominated five to eight-membered ring [1,2-a] fused benzimidazoles and [1,4]oxazino[4,3-a]benzimidazoles are synthesized in mostly high yields of >80% using the reaction of hydrogen peroxide and hydrohalic acid with commercially available o-cyclic amine substituted anilines. Domestic bleach with HCl is also capable of a one-pot ring-closure and chlorination

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

Clinical usefulness of doxorubicin (DOX) is limited by the occurrence of multidrug resistance (MDR) associated with the presence of membrane transporters (e.g. P-glycoprotein, MRP1) responsible for the active efflux of drugs out of resistant cells. Doxorubicin is a well-known bioreductive antitumour drug. Its ability to undergo a one-electron reduction by cellular oxidoreductases is related to the formation of an unstable semiquionone radical and followed by the production of reactive oxygen species. There is an increasing body of evidence that the activation of bioreductive drugs could result in the alkylation or crosslinking binding of DNA and lead to the significant increase in the cytotoxic activity against tumour cells. The aim of this study was to examine the role of reductive activation of DOX by the human liver NADPH cytochrome P450 reductase (CPR) in increasing its cytotoxic activity especially in regard to MDR tumour cells. It has been evidenced that, upon CPR catalysis, DOX underwent only the redox cycling (at low NADPH concentration) or a multistage chemical transformation (at high NADPH concentration). It was also found, using superoxide dismutase (SOD), that the first stage undergoing reductive activation according to the mechanism of the redox cycling had the key importance for the metabolic conversion of DOX. In the second part of this work, the ability of DOX to inhibit the growth of human promyelocytic-sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX) was studied in the presence of exogenously added CPR. Our assays showed that the presence of CPR catalysing only the redox cycling of DOX had no effect in increasing its cytotoxicity against sensitive and MDR tumour cells. In contrast, an important increase in cytotoxic activity of DOX after its reductive conversion by CPR was observed against HL60 as well as HL60/VINC and HL60/DOX cells

Methods of identification of dangerous sections on road network

W artykule przedstawiono metodę identyfikacji miejsc niebezpiecznych na sieci dróg bazującej na ryzyku, jako elemencie systemu zarządzania bezpieczeństwem infrastruktury drogowej na przykładzie sieci dróg krajowych. Przedstawiono doświadczenia zagraniczne identyfikacji miejsc niebezpiecznych i uwarunkowania prawne w Polsce wdrażające konieczność identyfikacji miejsc niebezpiecznych na sieci TEN-T. W ostatniej części zaprezentowano metodę klasyfikacji odcinków ze względu na: wypadki drogowe oraz bezpieczeństwo sieci dróg. Przedstawiono użyte miary, sposoby ich obliczania, granice klas ryzyka oraz wyniki prowadzonych prac na sieci dróg krajowych w latach 2010-2012.This paper presents a method to identify dangerous sections on the road network based on the risk management system as part of road infrastructure safety on the example of the national road network. In the first part of the experience abroad, which were prerequisites for the development of methods for identification of hazardous roads. The second part presents the legal conditions in Poland implementing necessary to identify dangerous places on the TEN-T road network. The final section presents a method classifying parts due to road accidents due to the classification of sections of the road network safety. Presented used measurement methods for calculating them, the limits of risk classes and the results of the work on the national road network in 2010-2012

Risk management method on the streets’ network in Warsaw

W artykule przedstawiono wykorzystanie oceny ryzyka do zarządzania bezpieczeństwem infrastruktury drogowej. W pierwszej części zaprezentowano uwarunkowania prawne oraz doświadczenia zagraniczne, które były przesłankami do opracowania metody oceny ryzyka na elementach liniowych i punktowych podstawowej sieci dróg miejskich w Warszawie. W drugiej części przedstawiono przyjęte założenia, opis obiektów analizy, okres analizy, specyfikację głównych problemów oraz wybrane miary ryzyka społecznego i indywidualnego. W trzeciej części opisano sposób przygotowania danych o sieci drogowej (podział na odcinki jednorodne, wybór skrzyżowań, przejścia dla pieszych) oraz natężeniu i bezpieczeństwie ruchu drogowego, które są niezbędne do wykonywania niniejszej metody oceny ryzyka. Dwie kolejne części obejmują procedurę przeprowadzenia klasyfikacji ulic i skrzyżowań ze względu na ryzyko społeczne i indywidualne. Ostatnia część artykułu zawiera opis procedury, której celem jest identyfikacja i ranking najbardziej niebezpiecznych odcinków, skrzyżowań i przejść dla pieszych na sieci ulic w Warszawie.The paper presents application of risk management methods in the road infrastructure safety management in cities. The first part outlines the legal conditions and international experience, which were premises for the development of risk assessment methods on the elements of linear and point infrastructure on the basic urban road network in Warsaw. The second part presents adopted assumptions, description of the objects of analysis, period of analysis, specification of the main problems and selected measures of collective and personal risk. The third section describes the methods of data preparation on road network (division into homogeneous sections, selection of intersections, pedestrian crossings) volume and traffic safety, which are necessary for the implementation of this risk assessment method. Two following parts include a procedure to carry out the classification of roads and intersections due to collective and individual risk. The last part of the paper describes the procedures to identify and rank the most dangerous sections, intersections and pedestrian crossings on the road network in Warsaw

Conformal step coverage of electron beam-assisted CVD of SiO2 and Si3N4 films

Includes bibliographical references (page 462).We have recently reported electron beam assisted chemical vapor deposition (CVD) of silicon dioxide (SiO2) and silicon nitride(Si3N4) films at low (200°C) substrate temperatures(1,2,3). Herein, we examine the ability of the electron beam deposition technique to conformally cover patterned aluminum and polysilicon steps

Active Benzimidazole Derivatives Targeting the MmpL3 Transporter in Mycobacterium abscessus.

The prevalence of pulmonary infections due to nontuberculous mycobacteria such as Mycobacterium abscessus has been increasing and surpassing tuberculosis (TB) in some industrialized countries. Because of intrinsic resistance to most antibiotics that drastically limits conventional chemotherapeutic treatment options, new anti-M. abscessus therapeutics are urgently needed against this emerging pathogen. Extensive screening of a library of benzimidazole derivatives that were previously shown to be active against Mycobacterium tuberculosis led to the identification of a lead compound exhibiting very potent in vitro activity against a wide panel of M. abscessus clinical strains. Designated EJMCh-6, this compound, a 2-(2-cyclohexylethyl)-5,6-dimethyl-1H-benzo[d]imidazole), also exerted very strong activity against intramacrophage-residing M. abscessus. Moreover, the treatment of infected zebrafish embryos with EJMCh-6 was correlated with significantly increased embryo survival and a decrease in the bacterial burden as compared to those for untreated fish. Insights into the mechanism of action were inferred from the generation of spontaneous benzimidazole-resistant strains and the identification of a large set of missense mutations in MmpL3, the mycolic acid transporter in mycobacteria. Overexpression of the mutated mmpL3 alleles in a susceptible M. abscessus strain was associated with high resistance levels to EJMCh-6 and to other known MmpL3 inhibitors. Mapping the mutations conferring resistance on an MmpL3 three-dimensional homology model defined a potential EJMCh-6-binding cavity. These data emphasize a yet unexploited chemical structure class against M. abscessus with promising translational development for the treatment of M. abscessus lung diseases